Submissions for variant NM_003242.6(TGFBR2):c.1526G>T (p.Gly509Val)

dbSNP: rs863223853

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000195860	SCV000250950	uncertain significance	not provided	2022-08-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33824467, 21949523)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000195860	SCV000698194	uncertain significance	not provided	2016-11-15	criteria provided, single submitter	clinical testing	Variant summary: The TGFBR2 c.1526G>T (p.Gly509Val) variant located in the protein kinase-like domain (via InterPro) causes a missense change involving a conserved nucleotide, which 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in one affected individual as a de novo event. A clinical diagnostic laboratory cites the variant as "pathogenic." In addition, other nearby TGFBR2 variants, Arg497Gln, Cys514Arg, and Ile510Ser, therefore suggesting the functional importance of this region. Taking all available lines of evidence into consideration, the variant of interest has been classified as a "Variant of Uncertain Significance - Possibly Pathogenic," until additional information becomes available.
Invitae	RCV000801577	SCV000941358	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-10-31	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 213935). This missense change has been observed in individuals with thoracic aortic aneurysm and dissection (PMID: 33824467; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 509 of the TGFBR2 protein (p.Gly509Val).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000801577	SCV001333530	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-02-14	criteria provided, single submitter	clinical testing
Department of Vascular Biology, Beijing Anzhen Hospital	RCV001374782	SCV001439499	likely pathogenic	Isolated thoracic aortic aneurysm	2018-09-01	criteria provided, single submitter	research